This document summarizes a lecture about analyzing the human microbiome and its relationship to human health. It discusses how the human body contains 100 trillion microbial cells that contain 100 times as many genes as human DNA. Recent advances now allow sequencing these microbial genomes and analyzing massive datasets to map the dynamics of the immune-microbial system and its connection to disease states. A key focus is generating high-resolution time series data of the gut microbiome and immune variables from large cohorts to understand how they influence conditions like inflammatory bowel disease. There is potential to design gut microbes as sensors of disease states by programming them to detect specific conditions.

1. “Assay Lab Within Your Body:
Biometrics and Biomes”
Invited Lecture
TSensors Summit
La Jolla, CA
November 12, 2014
Dr. Larry Smarr
Director, California Institute for Telecommunications and Information Technology
Harry E. Gruber Professor,
Dept. of Computer Science and Engineering
Jacobs School of Engineering, UCSD
http://lsmarr.calit2.net
1

2. Abstract
The human body contains 100 trillion microbial cells, each acting as sensors
and actuators. This is ten times the number of cells as human cells.
Furthermore, these microbes contain 100 times the number of DNA genes that
our human DNA does. The microbial component of this "superorganism" is
comprised of hundreds of species spread over many taxonomic phyla. To
decode the details of my own gut microbial ecology required high resolution
metagenomics sequencing at the Venter Institute, several CPU-decades of
supercomputer time, and data analysis using scalable visualization systems.
The human immune system is tightly coupled with this microbial ecology. I
have been collecting massive amounts of biomarker time series data from
inside my own body over the last six years. Analysis and graphing of this data
demonstrates the episodic evolution of this coupled immune-microbial system.
Can these microbes be thought of as one hundred trillion sensors, whose
abundance can read out health or disease states in the host body?

3. Intense Scientific Research is Underway
on Understanding the Human Microbiome
June 8, 2012 June 14, 2012
From Culturing Bacteria to Sequencing Them

4. 2012 Was the Year
the Human Microbiome Went Public

5. Your Body Contains One Hundred Trillion Microbes,
Each With Software Inside
Your Body Has 10 Times
As Many Microbe Cells As Human Cells
If
99% of Your
DNA Genes
Are in Microbe Cells
Not Human Cells

6. We Can Now Sequence the Microbes Genomes
Because of Exponential Decrease in Costs

7. Bacteria Are Programmable Sensors and Actuators
Tightly Coupled to the Immune System
May 2009

8. Bacterial Abundance
As Indirect Sensors of Disease

9. A Year of Sequencing a Healthy Gut Microbiome Daily -
Remarkable Stability with Abrupt Changes
Days
Genome Biology (2014)
David, et al.

10. To Map Out the Dynamics of Autoimmune Microbiome Ecology
Couples Next Generation Genome Sequencers to Big Data Supercomputers
• Metagenomic Sequencing
– JCVI Produced
– ~150 Billion DNA Bases From
Seven of LS Stool Samples Over 1.5 Years
– We Downloaded ~3 Trillion DNA Bases
From NIH Human Microbiome Program Data Base
– 255 Healthy People, 21 with IBD
• Supercomputing (Weizhong Li, JCVI/HLI/UCSD):
– ~20 CPU-Years on SDSC’s Gordon
– ~4 CPU-Years on Dell’s HPC Cloud
• Produced Relative Abundance of
– ~10,000 Bacteria, Archaea, Viruses in ~300 People
– ~3Million Filled Spreadsheet Cells
Illumina HiSeq 2000 at JCVI
SDSC Gordon Data Supercomputer
Example: Inflammatory Bowel Disease (IBD)

11. We Found Major State Shifts in Microbial Ecology Phyla
Between Healthy and Two Forms of IBD
Most
Common
Microbial
Phyla
Average HE
Average Ulcerative Colitis Average LS Average Crohn’s Disease

12. Time Series of My Gut Microbiome
Reveals Autoimmune Dynamics by Phyla
Therapy
Six Metagenomic Time Samples Over 16 Months

13. Visualizing Time Series of
150 LS Blood and Stool Variables, Each Over 5-10 Years
Calit2 64 megapixel VROOM

14. Only One of My Blood Measurements
Was Far Out of Range--Indicating Chronic Inflammation
Episodic Peaks in Inflammation
Followed by Spontaneous Drops
Normal Range
<1 mg/L
27x Upper Limit
Normal
Complex Reactive Protein (CRP) is a Blood Biomarker
for Detecting Presence of Inflammation

15. Adding Stool Tests Revealed
Oscillatory Behavior in an Immune Variable
Typical
Lactoferrin
Value for
Active
IBD
Normal Range
<7.3 μg/mL
124x Upper Limit
Hypothesis: Lactoferrin Oscillations
Coupled to Relative Abundance
of Microbes that Require Iron
Lactoferrin is a Protein Shed from Neutrophils -
An Antibacterial that Sequesters Iron

16. Fine Time-Resolution Sampling Also Reveals
Dynamical Innate and Adaptive Immune Dysfunction
Normal
Normal
Innate Immune System
Adaptive Immune System

17. Early Attempts at Modeling the Systems Biology of
the Gut Microbiome and the Human Immune System

18. Next Step: Time Series of Metagenomic Gut Microbiomes
and Immune Variables in an N=1000 Clinic Trial
Announced Last Friday!
Goal: Understand
“The Coupled Human Immune-Microbiome Dynamics
In the Presence of Human Genetic Predispositions
Inflammatory Bowel Disease Biobank
For Healthy and Disease Patients
Already 120 Enrolled,
Goal is 1500
Drs. William J. Sandborn, John Chang, & Brigid Boland
UCSD School of Medicine, Division of Gastroenterology

19. Can We Learn to Program Gut Microbes
to Become Direct Sensors of Disease?

20. Bacteria Have Been Designed
as a Variety of Sensors
Bacterial redox sensors
Jeffrey Green & Mark S. Paget

21. Microbial Biosensors
Have Very Wide Applicability
“In recent years,
a large number of microbial biosensors
have been developed
for environmental, food, and biomedical applications.”

22. Thanks to Our Great Team!
UCSD Metagenomics Team
Weizhong Li
Sitao Wu
Calit2@UCSD
Future Patient Team
Jerry Sheehan
Tom DeFanti
Kevin Patrick
Jurgen Schulze
Andrew Prudhomme
Philip Weber
Fred Raab
Joe Keefe
Ernesto Ramirez
JCVI Team
Karen Nelson
Shibu Yooseph
Manolito Torralba
SDSC Team
Michael Norman
Mahidhar Tatineni
Robert Sinkovits
UCSD Health Sciences Team
William J. Sandborn
Elisabeth Evans
John Chang
Brigid Boland
David Brenner